Pharmaceutical Composition for Regulation of Pancreatic Juice Secretion Comprising a LPA Receptor Modulator

Abstract

Pharmaceutical composition for regulation of pancreatic juice secretion characterized by comprising a lisophosphatidic acid (LPA) receptor modulator. Since an LPA receptor modulator has an effect of regulating the secretion of pancreatic juice, a compound acting on this receptor is useful in treating diseases in association with disorders in pancreatic juice secretion. For example, an LPA receptor agonist is useful in treating and/or preventing pancreatic diseases and obesity, while an LPA receptor antagonist is useful in treating and/or preventing maldigestion, constipation, diarrhea and cibophobia.

1 . A method for regulation of pancreatic juice secretion, which comprises administering a lysophosphatidic acid (LPA) receptor antagonist. 
     
     
         2 . The method according to  claim 1 , wherein the LPA receptor antagonist has an activity of accelerating pancreatic juice secretion. 
     
     
         3 . The method according to  claim 1 , wherein the LPA receptor antagonist is a compound represented by formula (B): 
       
         
           
           
               
               
           
         
         wherein one of R 1B  and R 2B  represents hydrogen, methylenehydroxy, carbomethyl, methylenamino, methyl, ethyl, isopropyl, benzyl or benzyl-4-oxybenzyl, and the other is necessarily hydrogen. 
       
     
     
         4 . The method according to  claim 1 , wherein the LPA receptor antagonist is a compound represented by formula (C): 
       
         
           
           
               
               
           
         
         wherein R 1C  represents alkyl, aryl, a heterocyclic group, alkyloxy, aryloxy, alkylthio or arylthio which may have a substituent(s), or halogen; 
         R 2C  represents alkyl, aryl, a heterocyclic group, alkyloxy or aryloxy which may have a substituent(s), or halogen; 
         R 3C  represents hydrogen, lower alkyl or halogenated alkyl; 
         R 4C  represents a group selected from the group consisting of (a) phenyl, aryl or a heterocyclic group which may have a substituent(s); (b) substituted or unsubstituted alkyl; and (c) substituted or unsubstituted alkenyl; 
         X represents oxygen or sulfur, and 
         wherein R 3C  and R 4C  taken with the carbon atom to which they bond may form a 5- to 10-membered cyclic structure, and when R 3C  is a hydrogen atom, R 4C  is a group other than methyl. 
       
     
     
         5 . The method according to  claim 4 , wherein the LPA receptor antagonist is methyl 3-({4-[4-({[1-(2-chlorophenyl)ethoxy]carbonyl}amino)-3-methyl-5-isoxazolyl]benzyl}sulfanyl)propanoate. 
     
     
         6 . The method according to  claim 1 , wherein the LPA receptor is EDG-2, EDG-4 or EDG-7. 
     
     
         7 . The method according to  claim 1 , wherein the LPA receptor is EDG-2. 
     
     
         8 . The method according to  claim 7 , wherein the EDG-2 antagonist is a compound represented by formula (B): 
       
         
           
           
               
               
           
         
         wherein one of R 1B  and R 2B  represents hydrogen, methylenehydroxy, carbomethyl, methylenamino, methyl, ethyl, isopropyl, benzyl or benzyl-4-oxybenzyl, and the other is necessarily hydrogen. 
       
     
     
         9 . The method according to  claim 7 , wherein the EDG-2 antagonist is a compound represented by formula (C): 
       
         
           
           
               
               
           
         
         wherein R 1C  represents alkyl, aryl, a heterocyclic group, alkyloxy, aryloxy, alkylthio or arylthio which may have a substituent(s), or halogen; 
         R 2C  represents alkyl, aryl, a heterocyclic group, alkyloxy or aryloxy which may have a substituent(s), or halogen; 
         R 3C  represents hydrogen, lower alkyl or halogenated alkyl; 
         R 4C  represents a group selected from the group consisting of (a) phenyl, aryl or a heterocyclic group which may have a substituent(s); (b) substituted or unsubstituted alkyl; and (c) substituted or unsubstituted alkenyl; 
         X represents oxygen or sulfur, and 
         wherein R 3C  and R 4C  taken with the carbon atom to which they bond may form a 5- to 10-membered cyclic structure, and when R 3C  is a hydrogen atom, R 4C  is a group other than methyl. 
       
     
     
         10 . The method according to  claim 9 , wherein the EDG-2 antagonist is methyl 3-({4-[4-({[1-(2-chlorophenyl)ethoxy]carbonyl}amino)-3-methyl-5-isoxazolyl]benzyl}sulfanyl)propanoate. 
     
     
         11 . A method for regulation of pancreatic juice secretion which comprises administering a lysophosphatidic acid (LPA) receptor agonist for treatment and/or prevention of pancreatic diseases or obesity. 
     
     
         12 . The method according to  claim 11 , wherein the pancreatic disease is congenital exocrine dysfunction, acute pancreatitis, chronic pancreatitis, pancreatic lithiasis, cholelithiasis, pancreatic tumor, pancreatic cyst or pancreatic diseases accompanied by abnormality in autonomic nervous system. 
     
     
         13 . The method according to  claim 1 , which is for treatment and/or prevention of pancreatic diseases or obesity. 
     
     
         14 . The method according to  claim 13 , wherein the pancreatic disease is indigestion, constipation, diarrhea, cibophibia or malabsorption syndrome.